Parkinson?s disease (PD) is relentlessly progressive and despite effective symptomatic therapy in the early stages of the illness most patients have substantial morbidity and disability. There is an urgent need to understand the etiology and pathogenesis of PD so that more effective symptomatic therapies and ultimately preventive therapies can be developed. Our hypothesis is that pathologic ?-synuclein spreads from the gut to the brain and contributes to a complex signaling network that results in the pathogenesis of PD and related disorders. The center will approach this hypothesis in a multidisciplinary manner. The center represents a multi-disciplinary, mechanistic approach involving interactive, productive investigators with complementary areas of expertise who have long been committed to studies of neurodegenerative diseases. Our center will integrate diverse advanced technologies within the Center to accelerate discovery. It will work collaboratively within the Udall Center Network to accelerate discovery of disease, new therapies and disease and progression biomarkers. Through the integration of the activities of the various disciplines the interrelationships will result in a greater scientific contribution than could be achieved if each project or Center investigation were pursued individually. The Johns Hopkins Udall Center will serve as a local and national resource for PD research including broad sharing of data and clinical and biospecimen resources and fostering community outreach activities. We will provide and coordinate training of young investigators in the pathogenesis and study of Parkinson?s disease and Parkinson?s syndromes. The Johns Hopkins Udall Center is focused on developing and characterizing of a novel pathologic ?-synuclein gut to brain model of PD (Project 1); investigating the role of PARIS site-specific gene methylation in the death of dopamine neurons in PD (Project 2); elucidating the role of parthanatos and the relationship to c-Abl activation in the pathogenesis of PD (Project 3); and to use our discoveries to develop and characterized c-Abl pathway molecules as disease and progression markers (Project 4) and ultimately new therapies. The development of a new animal model mimicking with some accuracy what is seen in clinical ?-synucleinopathies like PD and insights into the pathogenesis of PD as well as the discovery of biomarkers would not be possible without the Udall Center structure as it enables the integration of the activities of the various disciplines and projects so that the interrelationships will result in a greater scientific contribution than could be achieved if each project were pursued individually. We believe that our multi-disciplinary approach has the capacity to produce unique information concerning the mechanisms of neuronal injury in a novel animal model of PD that will lead to a better understanding of the role of pathologic ?-synuclein in pathophysiologic processes related to PD.